PROJECT SUMMARY The neurobiology of post-stroke sensorimotor recovery is not fully understood. Current research on stroke recovery focuses on two spatial levels of brain injury: the focal level (i.e., the lesion and brain structures directly affected by the stroke, such as the corticospinal tract) and the network level (i.e., brain structures distant from the lesion but affected via diaschisis). This proposal argues that a third level should be considered: global brain health (GBH), which is defined as the cellular, structural, and vascular integrity of the whole brain. Although GBH has recently been recognized as a crucial predictor of outcomes in conditions such as Alzheimer?s disease and traumatic brain injury, its role in stroke recovery is not well understood. Similarly, although focal and network effects of stroke injury have been well-studied, little is known about how stroke exerts global influences across the whole brain. The key scientific premise of this research is that (a) GBH modulates the overall neuroplastic resources that promote stroke recovery and (b) acute stroke injury causes global changes in brain health. The central hypothesis is that poor GBH is related to poor stroke outcomes, and conversely, that severe acute stroke injury is related to worsening of GBH. The rationale underlying the proposed research is that establishing GBH as a meaningful contributor to stroke recovery may stimulate new avenues of research and novel targets for therapeutic development. GBH will be estimated as indexed by four brain imaging measures linked to brain health (predicted brain age reflecting structural atrophy, severity of deep white matter hyperintensities, periventricular hyperintensities, and perivascular spaces). Aim 1 will utilize a large, retrospective stroke neuroimaging and behavioral database from the ENIGMA Stroke Recovery working group (N=627) to characterize the relationship between GBH and stroke outcomes in a cross-sectional chronic stroke population. Aim 2 will use a prospective, multi-site, longitudinal data collection (N=144) in individuals within three weeks and at three months after stroke to study how initial GBH relates to post-stroke brain repair and sensorimotor recovery. Aim 3 will use the same prospective dataset (N=144) to examine how the severity of acute stroke relates to longitudinal changes in GBH between 3 weeks and 3 months. With respect to key findings, we expect to show that GBH is related to sensorimotor outcomes and predicts the extent of early stroke recovery, and that GBH evolves in this context. The proposed work is innovative because it opens an entirely new framework in which to consider sensorimotor recovery after stroke. The results are expected to have an impact because they will advance our understanding of global influences on stroke recovery, and they will implicate GBH as a novel therapeutic target for potentiating recovery after stroke.